Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. Our major recent findings are as follows: 1) Extension and confirmation of our preliminary demonstration that continuous administration of combined estradiol and progesterone eliminates premenstrual syndrome in the context of ovarian suppressive therapy (i.e., it is the change in hormones that precipitates depression in this subgroup); 2) Evidence from our ovarian suppression protocol that women with a history of non-puerperal depression resemble women with premenstrual dysphoria (PMD) in that the introduction of reproductive steroids precipitates a depression; 3) Demonstration that the HPA axis [CRH-stimulated ACTH and exercise-stimulated cortisol] is upregulated in men compared with women under hypogonadal conditions, (thus contradicting assumptions that observed dimorphisms were consequent to activational effects of gonadal steroids); 4) Evidence that gonadal steriods have different regulatory effects on the HPA axis in men and women, with testosterone decreasing (men) and progesterone increasing (women) CRH-stimulated cortisol; 5) Women with PMS metabolize progesterone differently from control women, with the decrease in allopregnanolone levels during continuous progesterone administration associated with symptom development in women with PMS but not controls. These observations are of both theoretical and practical import. They more precisely define the physiologic trigger of PMS and help identify the physiological modulators of the HPA axis (which is disturbed in PMS). Additionally, the data with continuous hormone administration may not only inform our understanding of the relevant hormonal stimuli that precipitate PMS, but as well may suggest a new therapeutic strategy for the millions of women who suffer from this disorder.